Transforming growth factor-β suppresses metastasis in a subset of human colon carcinoma cells.
Transforming growth factor-β suppresses metastasis in a subset of human colon carcinoma cells.
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DOI：
10.1186/1471-2407-12-221
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发表时间：
2012-06-06
期刊：
影响因子：
3.8
通讯作者：
Brattain MG
中科院分区：
文献类型：
--
作者：
Simms NA;Rajput A;Sharratt EA;Ongchin M;Teggart CA;Wang J;Brattain MG
TGFβ信号传导通常与肿瘤起始的抑制相关，而其在转移中的作用通常与恶性肿瘤的进展相关。然而，我们在此提供了TGFβ信号传导的抗转移作用的证据。为了测试TGFβ信号传导对细胞存活和转移的重要性，我们比较了人结肠癌细胞系及其转移能力，所述人结肠癌细胞系是具有TGFβ应答的非致瘤性（FET），或具有TGFβ应答的致瘤性（FETα），或通过引入显性负性TGFβRII而具有消除的TGFβ应答的致瘤性（FETα/DN）。通过原位移植评估转移能力。通过组织学和成像评估转移集落形成。通过在非转移性FETα人结肠癌细胞中引入显性负性TGFβ受体II（TGFβRII）消除TGFβ信号传导，允许转移至远端器官，但重要的是不会减少原发部位的侵袭行为。在体外，FETα-DN细胞中TGFβ信号转导的缺失产生了响应细胞应激的增强的细胞存活能力。我们发现，增强的细胞存活与AKT磷酸化和细胞质表达的凋亡抑制剂（IAP）家族成员（生存素和XIAP），引起细胞保护作用，通过抑制半胱天冬酶在应激反应增加。为了证实TGFβ信号传导是转移抑制因子，我们在CBS转移性结肠癌细胞中挽救了TGFβ信号传导，这些细胞由于表观遗传抑制而失去了TGFβ受体表达。TGFβ信号传导的恢复导致这些细胞抑制远端器官中的转移性集落形成。这些结果表明，TGFβ信号传导在抑制已经进展到浸润性癌阶段的肿瘤的转移潜能中具有重要作用。本文所述的观察结果表明TGFβ信号在人结肠癌细胞中具有转移抑制作用。这引起了人们的担忧，即靶向抑制TGFβ信号传导的治疗在某些具有残留TGFβ肿瘤抑制活性的患者人群中可能是不谨慎的。
TGFβ signaling has typically been associated with suppression of tumor initiation while the role it plays in metastasis is generally associated with progression of malignancy. However, we present evidence here for an anti-metastatic role of TGFβ signaling. To test the importance of TGFβ signaling to cell survival and metastasis we compared human colon carcinoma cell lines that are either non-tumorigenic with TGFβ response (FET), or tumorigenic with TGFβ response (FETα) or tumorigenic with abrogated TGFβ response via introduction of dominant negative TGFβRII (FETα/DN) and their ability to metastasize. Metastatic competency was assessed by orthotopic transplantation. Metastatic colony formation was assessed histologically and by imaging. Abrogation of TGFβ signaling through introduction of a dominant negative TGFβ receptor II (TGFβRII) in non-metastatic FETα human colon cancer cells permits metastasis to distal organs, but importantly does not reduce invasive behavior at the primary site. Loss of TGFβ signaling in FETα-DN cells generated enhanced cell survival capabilities in response to cellular stress in vitro. We show that enhanced cellular survival is associated with increased AKT phosphorylation and cytoplasmic expression of inhibitor of apoptosis (IAP) family members (survivin and XIAP) that elicit a cytoprotective effect through inhibition of caspases in response to stress. To confirm that TGFβ signaling is a metastasis suppressor, we rescued TGFβ signaling in CBS metastatic colon cancer cells that had lost TGFβ receptor expression due to epigenetic repression. Restoration of TGFβ signaling resulted in the inhibition of metastatic colony formation in distal organs by these cells. These results indicate that TGFβ signaling has an important role in the suppression of metastatic potential in tumors that have already progressed to the stage of an invasive carcinoma. The observations presented here indicate a metastasis suppressor role for TGFβ signaling in human colon cancer cells. This raises the concern that therapies targeting inhibition of TGFβ signaling may be imprudent in some patient populations with residual TGFβ tumor suppressor activity.
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